SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade

Despite the genetic inactivation of SMARCA4, a core component of the SWI/SNF-complex commonly found in cancer, there are no therapies that effectively target SMARCA4-deficient tumours. Here, we show that, unlike the cells with activated MYC oncogene, cells with SMARCA4 inactivation are refractory to...

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Detalles Bibliográficos
Autores: Romero, Octavio A., Vilarrubi, Andrea, Alburquerque-Bejar, Juan J., Gomez, Antonio, Andrades, Alvaro, Trastulli, Deborah, Pros, Eva, Setien, Fernando, Verdura, Sara, Farré, Lourdes, Martín-Tejera, Juan F., Llabata, Paula, Oaknin, Ana, Saigi, Maria, Piulats, Josep Maria, Matias-Guiu, Xavier, Medina, Pedro P., Vidal, August, Villanueva, Alberto, Sanchez-Cespedes, Montse
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10459.1/467687
Acceso en línea:https://doi.org/10.1038/s41467-021-24618-3
https://hdl.handle.net/10459.1/467687
Access Level:acceso abierto
Descripción
Sumario:Despite the genetic inactivation of SMARCA4, a core component of the SWI/SNF-complex commonly found in cancer, there are no therapies that effectively target SMARCA4-deficient tumours. Here, we show that, unlike the cells with activated MYC oncogene, cells with SMARCA4 inactivation are refractory to the histone deacetylase inhibitor, SAHA, leading to the aberrant accumulation of H3K27me3. SMARCA4-mutant cells also show an impaired transactivation and significantly reduced levels of the histone demethylases KDM6A/UTX and KDM6B/JMJD3, and a strong dependency on these histone demethylases, so that its inhibition compromises cell viability. Administering the KDM6 inhibitor GSK-J4 to mice orthotopically implanted with SMARCA4-mutant lung cancer cells or primary small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), had strong anti-tumour effects. In this work we highlight the vulnerability of KDM6 inhibitors as a characteristic that could be exploited for treating SMARCA4-mutant cancer patients.SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade

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